Intermediates for producing semi-synthetic penicillins

ABSTRACT

Novel 6-APA, 7-ACA, and 7-ADCA derivatives are described which comprise phosphorylated derivatives of 6-APA, 7-ACA, or 7-ADCA and the corresponding acylated derivatives thereof. The novel compounds are prepared by the reaction of 6-APA, 7-ACA, 7-ADCA or a salt thereof with a phosphorus halide in the presence of an acid acceptor and subsequently acylating the thus formed phosphorylated compound, to form a phosphorylated acylated derivative which upon hydrolysis with water splits off the protective group(s) to provide the corresponding semi-synthetic penicillin or cephalosporin having useful antibacterial activity.

United States Patent [191 Sellstedt INTERNIEDIATES FOR PRODUCING SEMI-SYNTHETIC PENICILLINS [75] Inventor: John H. Sellstedt, Pottstown, Pa.

[22] Filed: Feb. 11, 1974 [21] App]. No.: 441,593

Related US. Application Data [62] Division of Ser. No. 197,142, Nov. 9, 1971, Pat. No.

[52] US. Cl..... 260/306.7 E; 260/2391; 260/243 C [51] Int. Cl. CO7d 99/16; CO7d 99/24 [58] Field of Search 260/243 C, 239.1, 306.7 E,

[56] References Cited UNITED STATES PATENTS 3,809,699 5/1974 Ishimaru 260/239] Primary Examiner-Nicholas S. Rizzo ABSTRACT Novel 6-APA, 7-ACA, and 7-ADCA derivatives are described which comprise phosphorylated derivatives of 6-APA, 7-ACA, or 7-ADCA and the corresponding acylated derivatives thereof. The novel compounds are prepared by the reaction of 6-APA, 7-ACA, 7- ADCA or a salt thereof with a phosphorus halide in the presence of an acid acceptor and subsequently acylating the thus formed phosphorylated compound, to form a phosphorylated acylated derivative which upon hydrolysis with water splits off the protective group(s) to provide the corresponding semi-synthetic penicillin or cephalosporin having useful antibacterial activity.

. 3 Claims, No Drawings INTERMEDIATES FOR PRODUCING SEMI-SYNTHETIC PENICILLINS This application is a division of applications Ser. No. 197,142 filed Nov. 9, 1971, now US. Pat. No.

This invention relates to novel phosphorylated 6- APA, 7-ACA, and 7-ADCA derivatives, acylated derivatives thereof and the process for their production.

One aspect of the present invention relates to the production of semi-synthetic penicillins and cephalosporins in high yields from compounds such as 6-amino penicillanic acid, 7-amino cephalosporanic acid, and 7-amino-3-desacetoxy cephalosporanic acid.

Another aspect of the present invention relates to the acylation of novel phosphorylated 6-amino penicillanic acids, 7-amino cephalosporanic acids, and 7-amino- 3-desacetoxy cephalosporanic acids in the absence of an acid acceptor.

Yet another aspect of the present invention relates to novel acylated and phosphorylated derivatives of 6- amino penicillanic acid, 7-amino cephalosporanic acid, 7-amino-3-desacetoxy cephalosporanic acid and related compounds.

These and other aspects of the present invention will become apparent from the following description.

In its broadest aspects the present invention covers compounds having the following structure:

R is a member selected from the class consisting of hydrogen and an organic acyl radical;

R is selected from the class consisting of hydrogen and a radical of the formula with the proviso that R and R are not both hydrogen;

R is a member selected from the class consisting of R, alkali metal (e.g. Na, K) and a tertiary amine;

R is a member selected from the class consisting of hydrogen, (lower)alkanoyloxy containing two to eight carbon atoms, and a quaternary ammonium radical.

R and R are each selected from the class consisting of (lower) alkyl, aryl, halo(lower)alkyl, aryl(lower- )alkyl; and R and R may be joined together to form with phosphorus, the ring i cunm x I wherein X is selected from the class consisting of oxygen, Cl-l and sulfur; m is an integer from 1 to 6; R is hydrogen or (lower) alkyl.

The preferred novel compounds of the present inven- R is selected from the class consisting of hydrogen and organic acyl;

. R is selected from the class consisting of hydrogen with the proviso that R and R are not both hydrogen;

R is selected from the class consisting of hydrogen and acetoxy.

The term (lower) alkyl as employed herein alone or in conjunction with other designated groups is in tended to encompass straight chain or branch chain alkyl groups consisting of from one through six carbon atoms (e.g. methyl, ethyl, propyl, butyl, isobutyl, hexyl, 2-ethylpropyl, etc.)

The term halogen as used herein is intended to encompass chlorine, bromine, iodine and fluorine. The term aryl encompasses monocyclic and bicyclic rings having six to 10 ring carbon atoms such as phenyl, naphthyl, etc. The term aryl(lower) alkyl is illustrated by benzyl, phenethyl, etc.

The term (lower)alkanoyloxy is illustrated by acetoxy, propionoyloxy and butanoyloxy. The term quaternary ammonium is illustrated by pyridinium, quinolinium, picolinum, etc. The term tertiary amine is illustra ted by any of the well-known radicals such as triethylamine, tribenzylamine, N-ethylpiperidine which are described in the penicillin and cephalosporin art as capable of forming an amine salt with the carboxyl group.

The acyl group defined by R is derived from an organic carboxylic acid or a suitable functional reactive derivative thereof.

When R is acyl, the preferred acyl radicals are selected from groups having the following formulae:

wherein:

R is selected from the class consisting of hydrogen,

(lower)alkyl and phenyl;

R and R are selected from the group consisting of hydrogen and (lower)alkoxy;

R is selected from the class consisting of hydrogen,

(lower)alkyl and phenyl;

---(cHz d il l R and R are selected from the class consisting of hydrogen and halogen; w

R and R are selected from the class consisting of hydrogen, halogen, (lower)alkyl, (lower)alkoxy, phenyl and phenoxy; J

a is an interger from O to l;

b is an interger from 0 through 5;

CH-C- I l ,DJL C1,,

DIAGRAM A (2 moles) (1 mole) Acylating agent H s hydrolysis I Acyl N--l 0= N lV(a) DIAGRAM B R-I-N 5 acld Q acceptor H halogen-P-R solvent acylating agent (2 moles) In the foregoing P ess the starting material (e.g. I

a phosphorus halide of formula II in the presence of inert organic solvent and an acid acceptor to form' a compound of formula III or VII respectively. This reaction is preferably carried out at a temperature above -l C. and not higher than about 25 C. The molar ratio of an acid binding agent to a starting material such as 6-APA is about 0.75 :2 and the molar ratio'of acid binding agent to a compound of f rmula II is 1:1.

Suitable acid binding agents are tertiary amines such as triethyl amine, dimethylaniline,"qu'inoline, pyridine, lutidine, alkali metal carbonates; alkaline earth carbonates or other acid binding agents known in the art. The preferred acid binding agent is a strong tertiary amine. As used herein strong amines are those characterized by. having dissociation constants in the range of from 10' to 10 or having comparable basicity, as distinguished from weak amines which are characterwith the amount of a compound of formula III becoming smaller as the molar ratio of a compound of formula ized by having dissociation constants'in the range of from 10* to 10"".

A wide range of anhydrous non-hydroxylic organic A compound of formula III and VII prepared accord I ing to this invention can be isolated by removing the hydrohalide base by filtration and distillation of the solvent, or if the intermediate is to beconverted at once to a penicillin or cephalosporin, the reaction mixture can be acylated directly without filtration or concentra tion.

The product orvproducts obtained from the reaction of a compound of formula I or VI with a phosphorylating agent is dependent on the molar ratio of the reactants as to whether an anhydride of the penicillanic acid is formed. Thus, if the molar ratio of a compound of formula II to formula I is greater than 1:1, the predominant material obtained is a compound of formula III, particularly as the molar ratio increases to about 2:1 and higher. On the other hand where-the molar ratio is 1:1 or less (e.g. 0.5:1), the predominant compound is period, i.e. between II is decreasedin relation to .the amount of '6-APA.

The preferred molar ratio of phosphorylating agent to the starting material such as a compound "of formula I or VI is greater than 1:1, preferably at least 2:1.

The fact that mixtures of phosphorylated compounds can be produced under certain reaction conditions does not interfere with the process of acylation and subsequent formation of the desired semi-synthetic penicillin or cephalosporin.

Novel phosphorylated acylated compounds within the scope of formula A and B may be prepared by the acylation of a compound of formula III or VII in accordance with the reaction sequence shown above in diagrams A and B, respectively.

Suitable acylating agents include carboxylic acid halides', carboxylic acid anhydrides, mixed anhydrides with other carboxylic or inorganic acids; esters such as thiol esters and phenol esters; lactones; and carboxylic acids with carbodiimides or N,N carboxyldiimidazoles. h 4 V Illustrative of some specific preferred acylating agents are phenoxyacetyl chloride, J 2,6- dimethoxybenzoyl chloride, benzene sulfonyl chloride, 2-phenoxypropionyl chloride, 2-phenoxy-butyl chloride, D(-)phenylglycyl chloride I-ICl, l-aminocyclopentane-carboxylic acid chloride HCI, l-aminocyclohexanecarboxylic acid chloride I-ICl, 2-amino-2- carboxyindane acid chloride I-ICl, 2-ethoxy naphthoyl bromide and 3-(2,6-dichlorophenyl)-5-methylisoxazole carbonyl chloride, etc.

I In carrying out the acylation step, it has been suprisingly found that an acid acceptorneed-not be present during the reaction. I-Ieretofore such a reagent was deemed essential for successfully carrying out the acylation procedure as illustrated by U.S. Pat. Nos. 3,595,855; 3,249,622. In addition, where a strong amine is used in reacting a compound of formula I with a compound of formula 'II, it is desirable to avoid the presence of any excessstrong amine because the strong amine has a deleterious effect on the yield of semisynthetic penicillin produced. The acylation process is carried out in the presence of an inert anhydrous organic solvent. Suitable solvents may be the same as earlier exemplified for the reaction producing the phosphorylated derivatives of 6-APA, 7-ACA, 7-ADCA, etc.

The acylated penicillins and cephalosporins of formulae IV and IX are readily hydrolyzed by treating with water, to split off the protective group from the amino group and the carboxyl group to form a semisynthetic penicillin or cephalosporin embraced by formulae V and X, respectively.

The acylation of a compound of formula III or VII first results in the formation of an intermediate of formula IV(a) or VIII, respectively. These intermediates rapidly convert to a compound of formula IV and IX, respectively as a result of expulsion of R Phalogen from the nitrogen atom. This expulsion is due to the presence of an anion (e.g. C1) upon formation of the intermediate of formula IV(a) or VIII, respectively, which attacks the phosphorus atom linked to the nitrogen. It is possible that the presence of a weak-base during the acylation would bind the anion and thereby avoid the expulsion of I R -Phalogen.

In the latter case hydrolysis of a compound of formula IV(a) or VIII, respectively, would result in direct for- -mation of a compound of formula V or X, rather than intermediate IV or IX.

The hydrolysis is carried out at a pH between 0.5 and 2 at a temperature below about 15, preferably between 0 and 5 C. The hydrolysis is carried out by treatment with water.

Where the acylating agent used is in the form of an acid addition salt, the penicillin or cephalosporin of formula V or X is recovered upon hydrolysis as an acid addition salt (e.g. chloride) which may then be converted to the free base by methods well known in the art. In the event the ultimate penicillin to be obtained is a-aminobenzyl penicillin (ampicillin), it has been found advantageous to change the chloride to an aryl sulfonic acid salt of the aminopenicillin either by adding an appropriate sulfonic acid to the reaction mixture comprising the selected organic solvent and water, or to the aqueous extracts separated as described immediately above. In this connection, a 25% excess of the sulfonic acid has been used to advantage in preparing the corresponding salt of ampicillin.

The aryl sulfonic salt of the a-aminobenzyl penicillin may then be converted to the penicillin per se by reaction with a base such as triethylamine or diethylamine in approximately 85% isopropanol. In the case of ampicillin specifically, the sulfonic acid salt, wet with water and ethyl acetate, may be added to isopropanol containing a molar equivalent of triethylamine at 80C., whereby the anhydrous form of ampicillin described and claimed in US. Pat. No. 3,144,445 is formed and collected by filtration from the hot mixture.

Alternatively, the corresponding penicillin may be obtained, but in hydrated form, by raising the pH of the aqueous reaction mixture containing the hydrochloride salt of said penicillin to the iso-electric point.

The starting materials defined by formula II may be prepared by procedures described in the literature. For example, the preparation of 2-chloro-1,3,2-dioxaphospholane is described by Lucas et al., J. Am. Chem. Soc. 72, 5491-5497 (1950). Other compounds within the scope of formula Il may be prepared by the procedures described by Brown et al., J. Chem. Soc. 878-881 (1970).

The following examples are given by way of i1lustration and are not to be construed as limitations of this invention.

EXAMPLE 1 D(-)a-aminobenzylpenicillin 6-Aminopenicillanic acid (10.81 g, 0.05 mole) is stirred for one-half hr. in ml. of dichloromethane at 05 C. containing 13.85 ml. of triethylamine. At O-5 C., a solution of 12.65 g. (0.1 mole) of 2-chloro- 1,3,2-dioxaphospholane in 50 ml. of dichloromethane is added over 1 hr., and the mixture is stirred an additional one-half hr. at 05 C. The resulting product is 6-( 1,3,2-dioxaphospholan-2-yl amino )penicillanic acid, 1,3,2-dioxaphospholan-2-yl ester. D-(- )phenylglycyl chloride hydrochloride (10.63 g., 0.05 mole) is added to the stirred mixture over 2 min., and stirring is continued for one-half hr. at 05 C. under nitrogen. The cooling bath is removed and the temperature is allowed to go to 17 C. and held at this temperature for a total acylation time of 3 hr. The resulting acylated product is 6-(2-amino-2- phenylacetamido)penicillanic acid, 1,3,2-dioxaphosphalan-Z-yl ester. The mixture is poured into 300 ml. of water at 0-5 C. and stirred for 15 min., with the pH going to 0.7. Celite is added, the mixture is filtered, and the filtrate is separated and the water layer (340 ml.) is bioassayed vs. S. Lutea. The addition of 5 ml. of this solution to 245 ml. of 1% pH 6 buffer gives an assay value of 700 y/ml. of ampicillin.

The B-naphthalene sulfonic acid salt is prepared from the 340 ml. of solution by adding ethyl acetate (40 ml.) and cooling to 0l0 C. followed by addition of 29.4 g. of a 37.68% solution of B-naphthalene sulfonic acid over 10 min. and holding the pH at 1.5 to 1.7 with the addition of 5N sodium hydroxide. This mixture is stirred overnight at 5(filtered, stirred in 60 ml. of ethyl acetate for 5 min., filtered and sucked dry, giving 27.3 g. the ,B-naphthalene sulfonic acid salt of D(-)aaminobenzylpenicillin. It was bioassayed vs. S. Lutea indicating the presence of 560 'y/mg. of ampicillin.

EXAMPLE 2 l-aminocyclohexane penicillin -Aminopenicillanic acid (43.25 g., 0.7 mole) is stirred in dichloromethane (400 ml.) containing triethylamine (55.6 ml., 0.4 mole) at room temperature until solution is complete. The temperature is lowered 'to 5 C., and 50.6 g. (0.4 mole) 2-chloro-1,3 2-dioxophospholane in 200 ml. of dichloromethane is added over 1 hr., and stirring is continued at 05 C. for onehalf hr. 1-aminocyclohexanecarboxylic acid chloride hydrochloride (40 g., 0.2 mole) is added, and the mixture is stirred while the internal temperature is allowed to slowly go to 10 C. over one-half hr., and the reaction is continued for an additional 2 /2 hr. at 10 C. The mixture is poured into 200 ml. of cold (05 C.) water and the mixture is stirred in an ice bath for 15 min. Isopropanol (160 ml.) and celite (15 g.) are added, the mixture is filtered by suction, andthe cake is washed with 40 ml. of isopropanol. The two-phase filtrate is poured into a 2 liter round bottom three-neck flask, and while stirring at 15-20 C., the pH is raised to 5.4-5.5 with 5N NaOl-l, giving white crystals of dihydrate of the above titled compound.

EXAMPLE 3 D(-)-a-aminobenzylpenicillin 6-Aminopenicillanic acid (43.25 g., 0.2 mole) is stirred in dichloromethane (400 ml.) containing triethylamine (55.6 ml., 0.4 mole) at room temperature until solution is complete. The temperature is lowered to 05 C., and 50.6 g. (0.4 mole) 2-chloro-1, 3,2-dioxophospholane in 200 ml. of dichloromethane is added over 1 hr., and continue to stir at 05 C. for one-half hr. D(-)Phenylglycyl chloride hydrochloride (43.6 g., 0.2 mole) is added over about 1 min., and the mixture is stirred at 05 C. for three-fourths hr. The ice bath is lowered so that only the lower 1-2 cm. of the flask is in the ice water, and the internal temperature is allowed to slowly (about 25 min.) go to 10 C., and then held at this point for a total temperature raising time and reaction time of 2 hr. The mixture is poured into 800 ml. of room temperature water, and the flask is rinsed with 200 ml. of water. The mixture is stirred with the vessel in an ice-bath for min., Super Cel is added, the mixture is filtered by suction, and the cake is washed with 200 ml. water. The layers are separated, and the aqueous phase is placed in a2 liter round bottom flask containing 200 ml. ethyl acetate. The internal temperature is lowered to 0l0 C. and the pH is adjusted to 2 by the addition of 5N sodium hydroxide. Then 100 ml. of a 37.7% B-naphthalene sulfonic acid solution is added in about 10 minutes while keeping the pH at 1.5 to 1.7 with 5N NaOl-l. After stirring 6 hr. at 05 C., and no stirring for 12 hr., the mixture is filtered, and the cake is washed with about 100 ml. of cold pH 2 water. After sucking as dry as possible the cake is stirred in 250 ml. of ethyl acetate for 5 minutes, the mixture is filtered, and the cake is washed with 2 X 50 ml. ethyl acetate, giving 137 g. of the above titled product. A portion of the sample is dried indicating 53.5% NVM with a corresponding yield of 66%, but bioassay vs. S. Lutea indicates 380 'y/mg. with a corresponding yield of 75%. This material is converted to anhydrous ampicillin in yield by the standard isopropanol triethylamine procedure as described in US. Pat. No. 3,487,073.

EXAMPLE 4 D(-)-a-aminobenzylcephalosporin In a manner similar to the process for preparation of ampicillin in Example 1, but using 7-amino-cephalosporanic acid (54.6 g., 0.2 mole) instead of 6- aminopenicillanic acid, D(-)-a-aminobenzylcephalosporin is isolated by adjusting the pH of the aqueous phase, obtained after filtration, to about 5.75.

EXAMPLE 5 naphthalene sulfonic acid salt of D(-)-a-aminobenzylpenicillin 6-Aminopenicillanic acid (21.7 g., 0.1 mole) is stirred in dichloromethane (200 ml.) at 0.5 C., and 14.0 ml. (0.1 mole) of triethylamine is added, and the mixture is stirred for one-half hr. At 05 C., a solution is dripped in of 2-chloro-l,3,2-dioxophopholane (12.7 g., 0.1 mole) in dichloromethane ml.) over a 1 hr. period and stirring is continued at 05 C. for one-half hr. D-(-)-phenylglycyl chloride hydrochloride (21.3 g., 0.1 mole) is added all at once and the mixture is stirred at 05 C. for 30 min. The ice bath is lowered so that only the lower 1-2 cm. of the flask is in the ice water, and the internal temperature is allowed to slowly go to 10 C. over about 2 hr., and the mixture is poured into 450 ml. of room temperature water, and the flask is rinsed with 60 ml. of water. The mixture is stirred with the vessel in an ice bath for 15 min., Super Cell is added, the mixture is filtered by suction, and the cake is washed with 100 ml. of water. The layers are separated, and the aqueous phase is placed in a 1 liter round bottom flask containing 100 ml. of ethylacetate. The internal temperature is lowered to 0l0 C. and the pH is raised to 2 by the addition of 5N NaOl-I. Then 60 g. of a 37% B-naphthalene sulfonic acid solution is added within 5 to 10 min. while keeping the pH at 1.5 to 1.7 with 5N NaOl-l. After stirring overnight at 05 C., the mixture is filtered, and the cake is washed with cold pl-l2 water (30 ml.). After sucking as dry as possible the cake is stirred in ml. of ethyl acetate for 5 min., the mixture is filtered, and the cake washed. twice with ethyl acetate, giving 38.2g. of the B-naphthalene sulfonic acid salt of D(-)-a-aminobenzylpenicillin. A portion of the sample is dried indicating the presence of 6.36 g. of NVM, with a corresponding 44% yield of the above titled product.

EXAMPLE 6 Following the procedure of Example 1, a series of phosphorylated penicillin compounds are prepared by reacting 2 moles of a 'ph'osphorylating agent of formula C with 1 mole of 6-APA to produce a compound of formula D.

R R --l X R. R, X R5, R, (a) CH3 CH3 Cl CH3 CH3 4 1 Cl 1 (Q) CHM) CH2 CH2 CH2 (d) S\ Cl S\ s s (e) C H C H Cl. c H (3 H O\ o\ (f) Cl o/ o (g) [cH, Cl [CH CHZ/ cnz EXAMPLE 7 Continued s s CH Following the procedure of Example 4, a series of i R H s phosphorylated penicillin compounds are prepared by R-i -x Rl N 0 reacting 2 moles of a phosphorylating agent of formula l b g OH C with 1 mole of 7-ACA or 7-ADCA to produce a compound of formula E. C F

(d) I: S Cl [s s S/ R5 R5 (c) C2H5 (2H5 Cl C2H5 2 s l I H 5 (r) 0 Cl R-PX R"-PN-- O\ O: N CH R R5 O=C-OL-R EXAMPLE 9 v C E Following the procedure of Example 4, a series of 5 a x 2 5 Rq X phosphorylated cephalosporin compounds are pre- (a) CH CH Cl H CH CH Cl pared by reacting 0.5 mole of a phosphorylating agent (b) H of formula C with 1 mole of 7-ACA or 7-ADCA to pro- O/ duce a compound of formula G. (6) 4 F H 4 b F Ii i (d). CH, CH da Cl OCCH; CH t'b CH2 Cl 5 5 EXAMPLE 8 Following the procedureof Example 1, a series of phosphorylated penicillin compounds are prepared by reacting 0.5 mole of a phosphorylating agent of formula C with 1 mole of 6-APA to produce a compound EXAMPLE 10 acylating agent hydrochloride salt of l-aminocyclopentane carboxylic acid chloride hydrochloride salt of l-aminocyclo-Z- hexene-l-carboxylic acid chloride hydrochloride salt of l-amino-lindane carboxylic acid chloride hydrochloride salt of Lamina-1,2,31,4- tetrahydronaphthoic acid chloride hydrochloride salt of l-amino-7-ethoxyl ,2,3.4-tetrahydrol -naphthoic acid chloride hydrochloride salt of 2-amino-2-indanecarboxylic acid chloride 7 hydrochloride salt of 2-amino-lphenoxy-Z-indane carboxylic acid chloride hydrochloride saltof l-amino-l,2,3,4-

tctrahydro-3 ,6-dimethyll -naphthoic acid chloride hydrochloride salt of l-amino-3-cyclopentene-l -carboxylic acid 3-( phenyl)-5-methyl-4-isoxazole- I carbonyl chloride 3-(2,6'-dichlorophenyl )-5-methyl- 4-isoxazole-carbonyl chloride NH; O

Continued CH T S CH R-N 0 J 0 ol: l O P acylating agent ocn 2,6-dimethoxy-benzoic acid chloride fi ocii Z-ethoxy-l -naphthoyl chloride O- H- a-phenoxy bulyric acid chloride f EXAMPLE 1 1 agents identified below are used to obtain the following acylated phosphorylated cephalosporins. Those having Following the procedure of Example 4, the acylating the amino group are obtained as the hydrochloride salt.

2-thien lacetic acid H y -CH C- S D(-)phenyl glycine chloride, H W hydrochloride (|IHC O-C-CH;,

0 O phenoxyacetic acid chloride H O-CH O-C-CH;

It is to be understood that the only limitation on the acyl radical of the synthetic penicillins and cephalosporins is that they be essentially non-toxic upon in vitro or in vivo application. I

The synthetic penicillins and cephalosporins prepared from the intermediates of the present invention have activity against gram positive and/or gram negapound chosen. Further, it will vary with the particular subject under treatment.

What is claimed is:

l. A method which comprises reacting a compound of the formula:

wherein:

R is selected from the class consisting of hydrogen,

alkali metal and tertiary amine; with a phosphorylating agent of the formula:

wherein:

R and R are each selected from the class consisting of (lower) alkyl, phenyl, naphthyl, phenyl(lower- )alkyl and naphthyl(lower)alkyl; R and R joined together with the phosphorus atom form the ring x is selected from the class consisting of oxygen, methylene and sulfur; m is an interger from 1 to 6; and R is selected from the class consisting of hydrogen and lower alkyl, said reaction being carried out in the presence of an acid binding agent.

2. A process according to claim 1 wherein R and R are joined together with the phosphorus atom to form the ring cn, x

R (CHz)mX and wherein X is oxygen.

3, A process according to claim 2 which comprises reacting 6-aminopenicillanic acid under anhydrous conditions and in the presence of an acid binding agent with a 2-halo-1,3,2-dioxaphospholane or a lower alkyl derivative thereof at a temperature between about lO and +25C; the molar ratio of said 2-halo-1,3,

2-dioxaphospholane or lower alkyl derivative thereof to said 6-aminopenicillanic acid being at least about 1:1. 

1. A METHOD WHICH COMPRISES REACTING A COMPOUND OF THE FORMULA:
 2. A process according to claim 1 wherein R5 and R6 are joined together with the phosphorus atom to form the ring
 3. A process according to claim 2 which comprises reacting 6-aminopenicillanic acid under anhydrous conditions and in the presence of an acid binding agent with a 2-halo-1,3,2-dioxaphospholane or a lower alkyl derivative thereof at a temperature between about -10* and +25*C; the molar ratio of said 2-halo-1,3, 2-dioxaphospholane or lower alkyl derivative thereof to said 6-aminopenicillanic acid being at least about 1:1. 